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Abdominal tuberculosis: experience with RNTCP category III antitubercular therapy.

Introduction

Abdominal tuberculosis, a type of extrapulmonary tuberculosis (EPTB), presents in a variety of forms. [1] Abdominal tuberculosis as a whole is more difficult to treat because it spreads contiguously and produces distortion of lumen and peristaltic activity that can permanently affect gastrointestinal function, predisposing the patient to lifelong strictures and small intestinal bacterial overgrowth. Abdominal tuberculosis as such has been put in seriously ill category III regimen because the therapy of abdominal tuberculosis throws up many challenges, especially those presenting with immune compromised and malnourished state. To accommodate all the accompanying challenges, it is prudent to keep the regimen flexible. Poor nutrition and phytosanitary standards are two such challenges in southeast Asian countries. Cost of therapy and compliance are the other important variables in treatment of abdominal tuberculosis because of its disturbingly symptomatic and prolonged course.

Short-course alternate-day antitubercular therapy (ATT) in this group of primarily infected young patients is an attractive option for both reducing cost and increasing compliance.

The purpose of this study was to study the 30- and 60-day efficacy of alternate-day therapy (with higher dose per person; weight immaterial between 30 and 60 kg) to daily regimen (with per kg based doses) in a selected group of patients with abdominal tuberculosis.

Materials and Methods

Patients presenting to gastroenterology (GI) outpatient department (OPD) with complaints of abdominal pain without GI symptoms were enrolled in a study to determine the cause of pain as functional or organic. Study duration was of 2 year from June 2013 onwards. Following investigations, colonoscopy with ileoscopy with biopsy and contrast-enhanced computerized tomography (CECT) of abdomen, ascitic fluid examination (where available), and X-ray chest (where supportive evidence required) were performed. Mantoux skin sensitivity test, tubercular culture, polymerase chain reaction (PCR) for tuberculosis, and GeneXpert tests were mostly not performed due to low sensitivity and high cost. Diagnosis was based on clinical inputs and a CECT of abdomen and/or colonoscopy evidence. Histopathology was performed on identified lesions. Normal mucosa of ileum was biopsied routinely.

Patients were divided to receive alternate-day therapy [H: isoniazid (600 mg), R: rifampicin (450 mg), Z: pyrazinamide (1500 mg), E: ethambutol (1200 mg)] or daily-weight-based regimen (H, 5 mg/kg/day; R, 10 mg/kg/day; Z, 20 mg/kg/day; E, 15 mg/kg/day) nonrandomly. Patients who weigh 60 kg or more received additional rifampicin (150 g) as per RNTCP guidelines. Weight-based daily regimen was given to patients with low body mass index, anemia, malnutrition, or an antecedent immunocompromised state. Alternate-day therapy was given mostly to those where identification of ileocecal tuberculosis/tubercular mesenteric lymphadenitis (IC/ML) seemed to be incidental or non-resolution of radiological evidence. A paired two-tailed z-value was calculated from the proportions of response to two regimens on a Web-based calculator (http://www.socscistatistics.com).

Result

During the study period, 54 patients were diagnosed with abdominal tuberculosis: 17 had tubercular ascites with cirrhosis of liver; 7 had military tuberculosis with pleural effusion with tubercular enteritis and/or tubercular ascites; 14 had tubercular ascites alone; 3 had tubercular colitis; 15 with tubercular enteritis presented with other comorbidities such as diabetes mellitus type II (6 patients), hypothyroidism (3 patients), pancytopenia (2 patients), seizure disorder (1 patient), acute renal failure with congestive cardiac failure (1 patient), and chronic diarrhea (2 patients).

Twelve patients with IC and ML tuberculosis were identified during the study period. Patients with ML tuberculosis were younger than those with IC tuberculosis. Eleven patients were identified with mesenteric lymphadenitis. Five patients had nonspecific lymphadenitis and responded to conservative treatment. Three patients were lost to follow-up. Four patients were prescribed daily antitubercular treatment because of their low weight. Three patients with IC tuberculosis with mild features of intestinal obstruction were found to have multiple ileal strictures. Most other patients with IC tuberculosis presented with right lower quadrant pain and did not respond to conventional analgesic and anti-infective treatment. These patients were then advised a CECT of abdomen wherein the diagnosis was confirmed.

Discussion

Functional abdominal pain syndrome (FAPS) or "only pain abdomen" is a common clinical presentation in young patients presenting to a GI OPD. Tuberculosis was found to be one of the foremost organic pathologies detected in this group of patients in a typically southeast Asian nation tertiary referral center OPD of Gastroenterology. Other diagnoses detected were liver hemangioma (2 patients), ureteric calculi (7 patients), diverticulosis (3 patients), urinary tract infection (10 patients), and gynecological conditions (6 patients).

Because of an abundance of patients with pulmonary tuberculosis in southeast Asian subcontinent, abdominal tuberculosis is found accompanying diseases such as chronic pancreatitis, extrahepatic portal hypertension, diabetes mellitus, hypothyroidism, and chronic renal disease. This latter situation causes considerable confusion as to the primary diagnosis and contribution of tuberculosis in morbidity. Considerable number of colonoscopies performed for diseases such as irritable bowel syndrome and irritable bowel disease also throws up a subset of patients where tuberculosis is incidentally detected. Hepatobiliary and pancreatic tuberculosis are the other types of enigmatic abdominal tuberculosis.

Moreover, it is often seen that EPTB especially abdominal tuberculosis is seen in immunocompromised states such as cirrhosis of liver, pancytopenia, malnutrition, diabetes mellitus, and alcoholism. Overall, abdominal tuberculosis especially gastrointestinal tuberculosis can affect the well-being of the patient and quality of life by affecting GI function and coping functions.

A characteristic of abdominal tuberculosis is its low diagnostic yield. Best estimates are for laparoscopic biopsy, approaching a healthy 60-80% in different series. In all the other modalities of investigation, the best estimates of PPV are 20-40%. Diagnostic laparoscopy is not a widely practiced diagnostic modality in southeast Asian nations, partly because of the extra workload it puts on the busy schedule of the attending surgeon. A study of abdominal tuberculosis from reputed hospital in a metro city could provide a histological or bacteriological evidence in only 64% patients with best available tools. [2] A combination of radiology such as CECT and endoscopy such as ileocolonoscopy coupled with few supporting clinical or lab evidences may be an acceptable strategy of identifying ileocecal and lymph node abdominal tuberculosis when other possibilities have been suitably (mostly clinically) excluded. [3,4] Cost of confirmatory evidence such as AFB positivity, caseating granuloma, or other ELISA or PCR tests is very high and time-consuming. Low sensitivity of these tests also proscribes its extensive reliance.

A therapeutic trial of ATT for 2-3 months has been an acceptable strategy of differentiating circumstantial evidence of abdominal tuberculosis from other differentials. Ultrashort ATT regimen of 3 months is often prescribed by gynecologist in tubo-ovarian mass or dysmenorrhea or lower abdominal pain patient to delineate the etiology in resource constrained settings.

Ileocecal tuberculosis (mural involvement as identified with CECT) is often accompanied with tubercular lymph adenitis. Isolated mesenteric tubercular lymphadenitis of differing patterns such as para-aortic, mesenteric, and peripancreatic and periappendiceal is mostly seen in younger patients without much mural involvement. [6] The types of involvement change with age of the patient and age of exposure. Both primary and post-primary abdominal tuberculosis can occur although post-primary tuberculosis is more common in young adult patients.

Very often, it is seen that nonspecific therapy with good nutrition also "cures" the condition in this group of patients. Usefulness of a short therapeutic nontubercular anti-infective challenge cannot be ignored before prescribing more decisive ATT.

Reported rate of drug-induced hepatitis in our study are fortuitously low. One reason for this may be relatively young age of patients. Hospitalized drug-induced liver injury due to ATT patients are usually those with multiple comorbidities. Average age of patients in this study population was 30 years whereas those with comorbidities admitted to GE ward was 44 years.

The apparent high response rate in alternate day therapy may be due to low number of patients and need to be confirmed with a larger longer study, which is ongoing. High overall symptom response rate may have to do to the rigorous clinical approach with which patients were clinically screened for abdominal tuberculosis. Probably only those with pathology of abdominal tuberculosis were being treated. A thorough counseling for dietary measures along with an adequate and productive follow-up before treatment to rule out nontubercular etiologies also contributed to the success.

One drawback of the study was that the patients could not be randomized between ileocecal and lymph node groups as per Table 1. The reason was that most patients with ML tuberculosis were adolescents with body weight less than 30 kg and thus not suitable to alternate day higher dose therapy.

Another drawback was that commercially available formulations were prescribed and thus it was not possible to assure exact dosing in each case. High-dose alternate-day therapy produced symptoms of gastritis in significant number of cases (Table2). Another study from a teaching hospital found similar incidence of dyspepsia in patients receiving fixed-dose alternate-day DOTS regimen. [7] It can be argued that formulations appropriately reducing the number of tablets in given case can further improve compliance and efficacy.

An offshoot of the alternate-day therapy was the realization by the patient that the abdominal discomfort was drug related so had to be tolerated. This also assured of better compliance due to better knowledge.

Thus, this study demonstrates that alternate-day highdose ATT was as efficacious as daily-weight-based ATT in a special subset of young adult patients of abdominal tuberculosis without significant comorbidities.

Conclusion

Self-administered DOTS alternate-day therapy according to RNTCP category III regimen is equally efficacious to daily-weight-based regimen in young adults with abdominal tuberculosis.

DOI: 10.5455/ijmsph.2016.03102015352

References

[1.] Rasheed S, Zinicola R, Watson D, Bajwa A, McDonald PJ. Intra-abdominal and gastrointestinal tuberculosis. Colorectal Dis 2007; 9:773-83.

[2.] Patel N, Amarapurkar D, Agal S, Baijal R, Kulshrestha P, Pramanik S, et al. Gastrointestinal luminal tuberculosis: establishing the diagnosis. J Gastroenterol Hepatol 2004; 19:1240-6.

[3.] Sinan T, Sheikh M, Ramadan S, Sahwney S, Behbehani A. CT features in abdominal tuberculosis: 20 years experience. BMC Med Imaging 2002; 2:3.

[4.] Sood R. Diagnosis of abdominal tuberculosis: role of imaging. J Indian Acad Clin Med 2001; 2:169-177.

[5.] Sanai FM, Bzeizi KI. Systematic review: tuberculous peritonitis--presenting features, diagnostic strategies and treatment. Aliment Pharmacol Ther 2005; 22:685-700.

[6.] Shah S, Thomas V, Mathan M, Chacko A, Chandy G, Ramakrishna BS, et al. Colonoscopic study of 50 patients with colonic tuberculosis. Gut 1992; 33:347-51.

[7.] Rajanandh MG, Nageswari AD, Ramasamy C, Dinesh V. Side effects of antitubercular drugs on directly observed treatment strategy under revised National Tuberculosis Control Programme in a teaching hospital. Global J Pharmacol 2012; 6(1):29-32.

Sunit K Shukla (1), Manoj Meena (2), Govind N Srivastava (3), Piyush Arora (2), Chetan B Patil (2), Ram N Meena (4)

(1) Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

(2) Department of Respiratory Medicine, Jawahar Lal Nehru Medical College, Ajmer, Rajasthan, India.

(3) Department of Tuberculosis and Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

(4) Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

Correspondence to: Manoj Meena, E-mail: manojchest@gmail.com

Received September 03, 2015. Accepted September 25, 2015
Table 1: Demographic profile of patients with IC and ML tuberculosis

Parameter                     IC TB        ML TB

Number                          8            4
Age (years)                 29 (15-45)   19 (12-26)
M/F                            4:5          2:1
Presenting complaints
  Predominantly pain            8            4
  Bloating/dyspepsia            6            3
  Features of SAIO              3            0
  Weight loss                   3            1
Physical finding
  Pallor                        3            1
  Tenderness over abdomen       7            2
  Carnett's test                3            1
  Lump                          4            0
  Mean weight (kg)              47           34
  Signs of weight loss          4            0
Investigations
  Hb (g%)                      10.5         11.2
  ESR (mm Hg)                   34           20
  CRP                        All < 3      All < 1
  Histopathology +              6            0
  Colonoscopy +                4/6           --
  CECT diagnosis               8/8          4/4

CECT, contrast-enhanced computerized tomography.

Table 2: Comparison of 30- and 60-day efficacy of daily
vs. alternate-day ATT

Parameters                  Treatment response,   p-value
                                 30 day

                           Daily     Alternate
                          (n = 8)   day (n = 4)

Response to therapy *       7/8         3/4       0.60
Improvement in pain         4/8         2/4       1.0
Significant weight gain     3/8         2/4       0.66
Reduction of lump           3/4         --
Adverse events
  Dyspepsia                  2           2        0.38
  Hepatitis                  0           0        0.0

Parameters                  Treatment response,   p-value
                                  60 day

                           Daily     Alternate
                          (n = 8)   day (n = 4)

Response to therapy *       8/8         4/4       1
Improvement in pain         8/8         3/4       0.13
Significant weight gain     6/8         2/4       0.38
Reduction of lump           4/4         --
Adverse events
  Dyspepsia                  3           3        0.0375 *
  Hepatitis                  1           0        0.47

* p < 0.05.
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Article Details
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Title Annotation:Research Article
Author:Shukla, Sunit K.; Meena, Manoj; Srivastava, Govind N.; Arora, Piyush; Patil, Chetan B.; Meena, Ram N
Publication:International Journal of Medical Science and Public Health
Article Type:Report
Geographic Code:9INDI
Date:Apr 1, 2016
Words:2083
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